Muscle protein and adipose catabolism after burn or other life-threatening injury is likely an acute, adaptive response to preserve organ function and promote survival. However, persistent cachexia in the convalescent phase is pathological in itself. Hypermetabolism and catabolism of skeletal muscle mass for up to 2 years after burn injury renders patients vulnerable to injury and infection, retards wound healing, reduces overall function and diminishes quality of life. Myostatin is a skeletal muscle-specific member of the Transforming Growth Factor- 2 superfamily and a potent, tonic muscle growth inhibitor .Our long term goal is to define the key regulatory pathways mediating muscle wasting after burn injury for the purpose of developing therapeutics. The objective of this application is to determine the role of the myostatin signaling pathway in muscle wasting after burn injury. Our hypothesis is that myostatin and related ligands promote muscle wasting after burn injury, and that altering myostatin family signaling after burn will change burn survival, muscle mass and function. In the acute post-burn period, myostatin signaling and muscle wasting may facilitate survival. In the longer term, myostatin action and muscle wasting becomes maladaptive, reducing function and increasing vulnerability. We base this hypothesis on considerable preliminary data. We developed a mouse model of burn injury that causes long- term hyperinflammation and catabolism despite hyperphagia. Myostatin family signaling was increased in skeletal muscle after burn. Paradoxically, myostatin null mice exhibited enhanced wasting but also increased survival after burn. Administration of a myostatin inhibitor reduced muscle loss after burn injury. However, abolishing signaling from all myostatin-family ligands using a dominant negative ACVR2B transgenic resulted in 100% mortality after burn injury. These data indicate that myostatin family signaling plays an important, temporally regulated role in muscle size control after burn-injury. To study myostatin in burn, we have assembled a highly interactive, multidisciplinary team. The PI is a molecular biologist and expert in muscle wasting and the co-investigators are the world-leader in myostatin research, a highly accomplished academic surgeon-scientist, and the director of one of the country's largest and busiest burn centers. Each is necessary for the ultimate translation of these findings to therapeutics. Together we will determine the role of myostatin and myostatin-related ligand activity in burn-induced muscle wasting; determine the role of the myostatin family receptors ACVR2 and ACVR2B in burn-induced muscle wasting; and determine the role of SMAD2 activity in burn-induced muscle wasting. PUBLIC HEALTH RELEVANCE: The studies will result in new insights into the molecular pathways by which myostatin and related ligands regulate muscle mass in normal physiology and in burn wasting. They are essential pre-clinical studies for determining the potential clinical benefit of modulating myostatin for increasing survival and function after burn injury.